Targeting FOXM1 in chemo-resistant monocytic AML

点击翻译按钮获取中文摘要

The outcomes for acute myeloid leukemia (AML) have remained poor for the past 30 years. 20- 40% of patients fail to achieve remission with induction chemotherapy, and 50-70% of patients who achieve a complete remission relapse within 3 years. A major breakthrough in dissecting out prognostic subgroups came with the discovery of the nucleophosmin (NPM1) mutation in 40%-60% of cytogenetically normal (CN)-AML cases. In subsequent analyses it has been shown that AML patients with wild-type FMS-like receptor tyrosine kinase (FLT3), bearing mutated NPM1 (NPM1mut) showed improved overall survival and relapse-free survival. We proposed that mutated NPM1 (NPM1mut) confers this advantage in AML-M5 via sequestration of FOXM1 in the cytoplasm where FOXM1 is inactive. In preliminary experiments we showed that FOXM1 inhibitors: STL427944 (C25H23N7O4) and benzamil hydrochloride (C13H15Cl2N7O) suppress nuclear FOXM1 in AML-M5 cell lines. We propose the following specific aims: Specific Aim 1. To investigate specificity of STL427944 and benzamil hydrochloride for FOXM1 suppression and their anticancer activity in AML-M5 cell lines. First, we will use monocytic AML-M5 cell lines THP1, AML-193 and U937 to confirm our preliminary data that these drugs inhibit FOXM1 in AML-M5 cell lines. Next, we will treat AML-M5 cells with STL427944 and benzamil hydrochloride and will compare FOXM1 regulatory network using RNA-seq in parental and treated cells. We will also perform ChIP-seq experiments and we will identify direct targets of FOXM1 by comparing RNA-seq and ChIP-seq experiments. Thus, as the result of data integration, we expect to have a prioritized list of functionally significant genes that belong to FOXM1 network. Specific Aim 2. To determine pharmacokinetics and efficacy of novel FOXM1 inhibitors in AML-M5 mouse models. First, we will determine toxicity, pharmacokinetics (PK) and bioavailability of STL427944 and benzamil hydrochloride. To determine toxicity of STL427944/benzamil in mice and also pharmacokinetics (PK) and bioavailability we will collaborate with the Toxicology Research Laboratory (TRL), STL427944 and benzamil will be tested in CD-1 mice. Clinical signs of toxicity and mortality will be assessed for 2 days, twice a day. To establish efficacy of STL427944/benzamil as anticancer drugs for AML-M5 in mice we will treat AML-M5 xenograft tumors with MTD of STL427944/benzamil in combination with cytarabine or venetoclax.. We will establish several groups of murine AML xenografts using different AML-M5 cell lines and will treat them with that STL427944/benzamil hydrochloride individually or in combination with cytarabine or venetoclax. The mice will be monitored for 12 weeks and disease phenotype, and life expectancy and FOXM1 levels will be compared with vehicle treated mice. These experiments will be crucial to determine whether STL427944/benzamil could be further developed as the anticancer drugs for AML-M5 patients.